POS1147 EFFICACY OF CENERIMOD IN PATIENTS WITH HIGH IFN-1 GENE EXPRESSION SIGNATURE AND HIGH ANTI-DSDNA ANTIBODY LEVELS: POST-HOC ANALYSIS FROM A PHASE 2 STUDY
Authors: A. Askanase, D. D’cruz, K. Kalunian, J. Merrill, S. Navarra, C. Cahuzac, P. Cornelisse, D. Strasser, L. Trokan, O. Berkani
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Cenerimod is an orally active, selective sphingosine 1-phosphate (S1P) 1 receptor modulator under investigation for the treatment of systemic lupus erythematosus (SLE). The Phase 2 CARE study (NCT03742037) did not meet its primary endpoint after adjustment for multiplicity, but patients treated with cenerimod 4 mg showed reduced disease activity versus placebo after 6 months.<sup>[1]</sup> Along with prior findings that type-1 interferon (IFN-1) activation is a robust biomarker of SLE disease activity and that an elevated IFN-1 signature associates with autoantibodies and more severe disease, cenerimod reduces plasma levels of IFN-α and leads to decreased circulating B and T cells in patients with SLE, suggesting effects on both innate and acquired immune responses. <h3>Objectives</h3> These post-hoc analyses evaluated the efficacy of cenerimod in subpopulations of patients with SLE. <h3>Methods</h3> CARE randomised 427 patients with SLE to once-daily cenerimod (0.5, 1, 2 or 4 mg) or placebo. At month (M) 6, patients receiving 4 mg cenerimod were re-randomised to placebo or cenerimod 2 mg for the subsequent 6 months, while all other groups continued their initially assigned treatment to M12. The primary endpoint was change from baseline to M6 in SLEDAI-2K score modified to exclude leukopenia (mSLEDAI-2K) due to the mechanism of action of cenerimod. Post-hoc analyses were performed in patients with high IFN-1 gene expression signature or anti-dsDNA levels ≥30 IU/mL. IFN-1 gene expression signature was based on the expression of four genes (<i>IFI27</i>, <i>RSAD2</i>, <i>HERC5</i>, <i>IFIT1</i>). <h3>Results</h3> Primary results from the CARE study were presented at ACR 2022.<sup>[1]</sup> The primary endpoint was not met (nominal P=0.0291 for cenerimod 4 mg vs placebo). At baseline, 207 patients (51%) in CARE had high IFN-1 gene expression signature, including 36 (45%) and 40 (50%) randomised to cenerimod 4 mg and placebo, respectively. Anti-dsDNA antibody levels ≥30 IU/mL were noted in 86 patients (20%), including 21 (25%) and 15 (17%) for cenerimod 4 mg and placebo, respectively. There was an association between high IFN-1 gene expression signature and high anti-dsDNA levels, with more than 75% of patients with anti-dsDNA levels ≥30 IU/mL having high IFN-1 gene expression signature. Reduction in mSLEDAI-2K from baseline to M6 for the cenerimod 4 mg group was greater in patients with high IFN-1 gene expression signature and high anti-dsDNA antibody levels versus the overall population (Figure 1A). Similarly, the proportion of SRI-4 responders at M6 was higher in patients with high versus low IFN-1 gene expression signature (70% vs 41% for cenerimod 4 mg; 46% vs 43% for placebo). Patients with high IFN-1 gene expression signature treated with 4 mg cenerimod showed reduced IFN-α and anti-dsDNA levels at M6 versus baseline. At M6 resolution of alopecia was reported by more patients with high versus low IFN-1 gene expression signature (38% vs 26% for cenerimod 4 mg; 14% vs 7% for placebo), as were resolution of arthritis (57% vs 28% for cenerimod 4 mg; 38% vs 42% for placebo) and reduction in mucosal ulcers (80% vs 67% for cenerimod 4 mg; 41% vs 41% for placebo) on the mSLEDAI-2K. However, there was no treatment effect observed in rash. <h3>Conclusion</h3> Treatment with cenerimod 4 mg resulted in greater reductions of disease activity versus placebo at M6 in patients with high IFN-1 gene expression signature or high anti-dsDNA antibody levels at baseline. Cenerimod treatment also reduced levels of IFN-α protein and anti-dsDNA antibodies in these patients. Two Phase 3 studies of cenerimod 4 mg in SLE are underway. <h3>Reference</h3> [1]Askanase A et al. Efficacy and Safety of Cenerimod in Patients with Moderate to Severe Systemic Lupus Erythematosus (SLE): A Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled, Dose-Finding Phase 2b Trial. Arthritis Rheumatol 2022; 74 (suppl 9):3293–7. <h3>Acknowledgements</h3> o This study was sponsored by Idorsia Pharmaceuticals Ltd. Medical writing support was provided by Anne Sayers (Idorsia Pharmaceuticals Ltd.) and funded by Idorsia Pharmaceuticals Ltd. We thank the patients for their participation and the CARE investigators for their involvement in patient care and contribution to the study. <h3>Disclosure of Interests</h3> Anca Askanase Consultant of: Abbvie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer. Provention, Remegen and UCB, David D'Cruz Consultant of: GSK, UCB, Vifor, Kenneth Kalunian Consultant of: Abbvie, AstraZeneca, Amgen, Aurinia, Biogen, BMS, Eli Lilly, Equillium, Genentech/Roche, Gilead, GSK, Idorsia, KangPu, Kezar, Novartis, Pfizer, UCB, Joan Merrill Consultant of: AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, Bristol Myers Squibb, EMD Serono, Genentech, Gilead, GlaxoSmithKline, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas, Grant/research support from: Astra Zeneca, Bristol Myers Squibb, and GlaxoSmithKline, Sandra Navarra Speakers bureau: Janssen, GlaxoSmithKline, Roche, Consultant of: Astellas, AstraZeneca, Aurinia, Biogen, Boehringer Ingelheim, Idorsia, Grant/research support from: Novartis, Eli Lilly, Horizon Pharma, Clélia Cahuzac Employee of: Employee of Idorsia Pharmaceuticals Ltd., Peter Cornelisse Employee of: Employee of Idorsia Pharmaceuticals Ltd., Daniel Strasser Employee of: Employee of Idorsia Pharmaceuticals Ltd., Luba Trokan Employee of: Employee of Idorsia Pharmaceuticals Ltd., Ouali Berkani Employee of: Employee of Idorsia Pharmaceuticals Ltd.